Characterization of the Analgesic Effects of Paracetamol and Caffeine Combinations in the Pain‐induced Functional Impairment Model in the Rat

Abstract— The analgesic activities of paracetamol (100, 178, 316 and 562 mg kg⁻¹), caffeine (10,18, 32 and 56 mg kg⁻¹) and combinations of these doses were tested on a pain‐induced functional impairment model in the rat. Dysfunction of the right hind limb was induced by an intra‐articular injection of 30% uric acid in the knee. Drugs were given orally and the recovery of functionality over time was considered as an expression of analgesia. Paracetamol alone induced a dose‐dependent analgesic effect whereas caffeine alone did not show any activity at the assayed doses. Combinations of 316 mg kg⁻¹ paracetamol with either 10, 18, 32 or 56 mg kg⁻¹ caffeine yielded analgesic effects significantly greater than that of paracetamol alone. The highest potentiation was observed with a paracetamol‐caffeine mixture of 316–32 mg kg⁻¹. Caffeine coadministration, however, did not significantly change paracetamol plasma levels. No potentiation was obtained with other combinations. Paracetamol plasma levels and analgesic effect observed with administration of 316 mg kg⁻¹ paracetamol alone or 316–32 mg kg⁻¹ of paracetamol‐caffeine were fitted to the sigmoidal E_max model according to the Hill equation. The curves obtained were parallel, but that of the combination was shifted to the left. It is concluded that caffeine is able to potentiate the analgesic effect of paracetamol by a pharmacodynamic mechanism, but this only occurs at certain dose combinations. 1993 Royal Pharmaceutical Society of Great Britain